Cleft lip and/or palate (CL/P) is a common birth defect with a complex ideology and large health burden. The effects of CL/P on birth outcomes such as low birth weight and prematurity have been understudied. It is also unclear if primary birth outcome determinates such as maternal health might effect future development differently, for instance, with CL/P. On the other hand, maternal smoking has been reported in several previous studies to increase the risk for CL/P. Yet these studies have ignored the potential self selection of smoking based on anticipated pregnancy risks and outcomes which may lead to bias in the effects of smoking on CL/P risks when unaccounted for. This application aims at evaluating the effects of isolated CL/P as one group as well as by cleft type on birth outcomes including low birth weight and prematurity and applies quantile regression models to estimate differences in birth weight quantiles between infants with and without CL/P adjusting for several potential confounders. The effects of primary birth outcome determinates including maternal health and fertility history characteristics, for example, infant sex and the ancestry and prenatal input such as prenatal care will be studied specifically for infants with CL/P and compared to estimates for infants without CL/P to further understand developmental differences related to CL/P and identify approaches to streamline prenatal care and counseling programs available to women with pregnancies that are afflicted with CL/P. These two aims will use South American birth registry data collected by the Collaborative Latin American Study of Birth Defects (ECLAMC) on samples of about 5,000 cases with isolated CL/P and about twice as many controls which is a unique and appropriate data source for these Aims. A third aim of the project is to estimate the effects of smoking on CL/P risk accounting for self selection which is achieved by applying an instrumental variable model that uses instruments which in this project are genetic variance that have been linked to smoking, yet otherwise are unrelated to CL/P to exploit variation and smoking that is free from self selection and confounding. For this aim, the applicants will use environmental and genetic data from about 430 cases with isolated CL/P and 760 control samples recruited to the Norway Facial Cleft Study, a population survey of most CL/P cases that were born in Norway in 1996-2001. These data also have strong advantages including a large sample size and the fact that the smoking genetic variances of interest have already been typed in these samples. A proposed instrumental variable model provides a powerful analytical approach that may be extended to study the effects of maternal smoking on other newborn birth defects such as low birth weight and prematurity. This project studied the effects of cleft with a palate or birth outcomes and aims at identifying potential approaches to include prenatal care programs for afflicted pregnancies. Another aim is to obtain consistent estimates of the effect of maternal smoking or cleft lip and palate risk. The proposed model can be applied to study other newborn disorders. [unreadable] [unreadable] [unreadable]